Fetal Cardiovascular Control Research Articles

Radical change for the fetus

Fetal cardiovascular and metabolic responses to hypoxaemia are central to intact fetal survival and are well conserved across species. For instance, although human labour is commonly associated with transient fetal hypoxaemia caused by uterine contractions, the prevalence of a common manifestation of fetal hypoxaemia, neonatal hypoxic–ischaemic encephalopathy (HIE), is low. It is only when fetal physiological compensations are overwhelmed or blunted that tissue damage occurs, leading to fetal death or long-term disability, such as cerebral palsy. One aspect of the acute cardiovascular defence, the redistribution of cardiac output to favour essential organs such as the adrenals, myocardium and brain, is also central to fetal survival if hypoxaemia is maintained, as observed with fetal growth restriction as a result of placental dysfunction. Any major advance in understanding the mechanisms underlying these responses is therefore to be welcomed. In this context, the work published by Herrera, Kane and colleagues (Herrera et al. 2012) in this issue of The Journal of Physiology, is the latest example of importance. This research group has discovered that in the fetal circulation, reactive oxygen species (ROS) interact with nitric oxide (NO) to modify vascular function, promoting a vascular ‘oxidant tone’ under basal and stimulated conditions. This oxidant tone or fraction can be manipulated in either direction, with consequent changes in vascular resistance and thereby blood flow. Hence, during basal conditions, administration of antioxidants, such as vitamin C or melatonin, into the fetal circulation quenches ROS and increases NO bioavailability. This leads to a decrease in umbilical vascular resistance and an increase in umbilical blood flow, demonstrating that the oxidant tone maintains umbilical perfusion under check even under basal conditions (Thakor et al. 2010a). During acute fetal hypoxia, hypoxia-induced ROS limits NO bioavailability in the fetal peripheral circulation. This effect contributes to the chemoreflex and endocrine constrictor mechanisms that redistribute the fetal cardiac output away from non-essential vascular beds towards the brain, i.e. the oxidant tone contributes to the fetal brain sparing effect during acute hypoxia (Thakor et al. 2010b). Most recently, Giussani's group has also shown that fetal treatment with statins, another strategy to increase NO bioavailability, also modifies the vascular oxidant tone with predictable consequences on the fetal peripheral vasoconstrictor response to acute hypoxia (Kane et al. 2012). Further, maternal treatment with antioxidants in rat pregnancy complicated by fetal chronic hypoxia was protective and increased birth weight (Richter et al. 2012). The current study in this issue of The Journal traces the origins of this pro-oxidant mechanism. Xanthine oxidase (XO) is known to be stimulated by hypoxia and may act as a source of ROS, limiting NO bioavailability. To assess its role in fetal cardiovascular control a high dose of allopurinol, a xanthine oxidase inhibitor, was given to pregnant ewes and the fetal response observed under basal and stimulated conditions. Maternal allopurinol caused an increase in umbilical arterial blood flow and conductance, providing proof of concept that XO-derived free radicals have a role on the regulation of fetal cardiovascular function under basal conditions. XO blockade also blunted the pressor response in the femoral circulation to phenylephrine, suggesting that XO-generated ROS may also have a role in the pressor and peripheral vasopressor responses to acute hypoxia. The data also have potential translational relevance. ROS are implicated in the aetiology of maternal pre-eclampsia and of fetal brain injury leading to a number of reported or ongoing trials where anti-oxidants have been given to the mother during pregnancy. In particular, allopurinol has been tested as a potential neuro-protectant in neonates with HIE and is now being assessed as an antenatal treatment (Kaandorp et al. 2010). The study by Herrera et al. shows that allopurinol in very high doses in sheep can have potentially beneficial as well as detrimental effects. The associated increase in umbilical blood flow will improve placental efficiency and increase fetal substrate delivery. However, blunting the fetal peripheral vascular response to pressor agents or acute hypoxia would be detrimental if it meant the fetus could not maintain perfusion to the cerebral circulation during a hypoxic challenge. However, there is a caveat in this line of thinking. While allopurinol-induced increases in NO bioavailability may depress constriction in fetal circulations that vasoconstrict during hypoxia (e.g. femoral), it may actually maintain or enhance blood flow in fetal circulations that vasodilate during acute hypoxia (e.g. cerebral). The maintenance of perfusion pressure is therefore critical. Studies that include parallel measurement of peripheral and cerebral blood flow in the sheep fetus during acute hypoxia in the presence of antioxidant treatment in doses that are administered to humans are required before the potential consequences of fetal anti-oxidant treatment are known.

P1-21 The effect of acute maternal hypoglycaemia on fetal cardiovascular control

Aims: To investigate the effect of acute maternal hypoglycaemia on fetal cardiovascular (CV) function, as a sub-optimal environment in utero has been implicated in the development of CV disease in adult life. Subjects: Fetal sheep (n = 7) were studied in utero at 125 and 126 days gestational age (dGA, term = 147 days) following implantation of vascular catheters and an umbilical cord occluder at 119 dGA. Study design: Fetal CV parameters were measured during a maternal saline (day 125) and insulin (day 125) infusion. Fetal CV function was assessed by: (a) generating a dose response curve to angiotensin II; (b) a 90 sec total umbilical cord occlusion; (c) administration of phenylephrine to assess baroreflex function. Outcome measures: (a) Area under the mean arterial blood pressure (MAP) response (AUC) to increasing doses of angiotensin II; (b) MAP and heart rate (HR) response to cord occlusion; (c) sensitivity and operating point of the baroreflex response. Results: Maternal insulin infusion resulted in maternal and fetal hypoglycaemia. (a) The angiotensin II MAP AUC was not affected by hypoglycaemia. (b) The increase in MAP and decrease in HR following a 90 sec cord occlusion was not affected by hypoglycaemia. (c) Hypoglycaemia resulted in reduced fetal baroreflex sensitivity (P Conclusions: Our finding of reduced fetal baroreflex sensitivity during fetal hypoglycaemia indicates altered CV homeostatic mechanisms. Such fetal adaptations to a poor intrauterine environment could contribute towards the development of altered cardiovascular phenotype in adult life.

Infection-related perinatal brain injury: the pathogenic role of impaired fetal cardiovascular control.

There is a growing body of evidence from clinical and epidemiologic studies that in utero exposure to infection plays an important role in the genesis of fetal or neonatal injury leading to cerebral palsy and chronic lung disease. Thus, after chorioamnionitis the incidence of immature neonates with periventricular white matter damage and periventricular or intraventricular hemorrhage is significantly elevated. Recent clinical and experimental data support the hypothesis that a fetal inflammatory response links antenatal infection with brain white matter damage and subsequent motor handicap. A variety of studies support the view that cytokines released during intrauterine infection directly cause injury to the immature brain. In this review, we provide evidence that in utero exposure to bacterial infection can severely alter fetal cardiovascular function, resulting in dysregulation of cerebral blood flow and subsequent hypoxic-ischemic brain injury.

The role of nitric oxide on fetal cardiovascular control during normoxia and acute hypoxia in 0.75 gestation sheep.

The role of nitric oxide in control of fetal cardiovascular functions and of cerebral blood flow during normoxia and acute hypoxia is only partially known. We studied the effects of nitric oxide synthase inhibition on the distribution of cardiac output in preterm sheep using N(omega)-nitro-L-arginine methyl ester (L-NAME). Thirteen fetal sheep were instrumented at a gestational age of 107 days. Three days later fetuses received L-NAME (n = 7) or vehicle infusion (n = 6). At 0 minutes, acute hypoxia was induced by occlusion of the maternal aorta for 2 minutes. Organ blood flows (microsphere method) and physiologic variables (fetal heart rate, mean arterial pressure [MAP], oxygen saturation, and pH) were measured at -75, -1, +2, +4, and +30 minutes. L-NAME caused bradycardia and an increase in MAP. A significant decrease in cardiac output by 32% occurred in the control group during the control period, which was consequently reflected in organ blood flows. L-NAME injection reduced cardiac output by 64% during normoxia. Blood flow to the fetal body, placenta, and cerebrum decreased by 62%, 66%, and 55%, respectively. During acute hypoxia, L-NAME did not change the redistribution of cardiac output toward the central organs. In the L-NAME group MAP increased, and fetal heart rate was maintained; in contrast, in controls MAP initially decreased and then returned to control values while fetal heart rate decreased. After hypoxia L-NAME delayed the recovery of cardiac output and blunted the increase in blood flow to the brain and heart. Although influenced by fetal stress after extensive instrumentation, the results of this study indicate that nitric oxide plays a role in fetal cardiovascular control during normoxia and acute hypoxia. Nitric oxide also mediates the increase in blood flow to the brain and heart immediately after hypoxia.

The Role of Nitric Oxide on Fetal Cardiovascular Control During Normoxia and Acute Hypoxia in 0.75 Gestation Sheep

The Role of Nitric Oxide on Fetal Cardiovascular Control During Normoxia and Acute Hypoxia in 0.75 Gestation Sheep

Effects of fetal behavioral states on renal sympathetic nerve activity and arterial pressure of unanesthetized fetal sheep.

Fetal behavior, renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were studied 1-3 days after surgery in seven fetal sheep (aged 127-136 days). Five behavioral states were defined from chart recordings of electrocortical (electrocorticographic; ECoG) activity and eye, limb, and breathing movements. Most records were of high-voltage ECoG (HV) or low-voltage (LV) ECoG with breathing (LVB); 6.7 +/- 1.7% were LV ECoG with no breathing (LV0). RSNA was lower in LV0 (P < 0.001) and greater in LVB than in HV (P < 0.05). MAP was lower in both LV states than in HV and when the fetuses went from LV to HV (P < 0.001 to P < 0.03). HR was highest in HV (P < 0.001). In HV and LVB and when the fetus went from LV to HV, MAP and HR were inversely related (P = 0.012-0.003). In LVB and from LV to HV there were direct relationships between MAP and RSNA (P = 0.0014, P = 0.08), and when the fetus went from LV to HV there was also an inverse relationship between HR and RSNA (P = 0.02). Thus fetal RSNA, MAP, and HR are affected by behavioral state as is fetal cardiovascular control. The increase in RSNA during fetal breathing showed that there was an altered level of fetal RSNA associated with fetal breathing activity.

Endotoxemia Severely Affects Circulation During Normoxia and Asphyxia in Immature Fetal Sheep

The purpose of the present study was to determine whether endotoxins (lipopolysaccharides, LPS) affect the fetal cardiovascular system in a way likely to cause brain damage. Thirteen fetal sheep were chronically instrumented at a mean gestational age of 107 +/- 1 days. After control measurements of organ blood flow (microsphere method), blood gases, and acid base balance were obtained, seven of 13 fetuses received LPS (53 +/- 3 microg/kg fetal weight) intravenously. Sixty minutes later, asphyxia was induced by occlusion of the maternal aorta for 2 minutes. Measurements of organ blood flows were made at -60, -1, +2, +4, +30, and +60 minutes. Unlike in the control group, after LPS infusion there was a significant decrease in arterial oxygen saturation (-46%; P <.001) and pH (P <.001). In LPS-treated fetuses the portion of combined ventricular output directed to the placenta decreased significantly (-76%; P <.001), whereas output to the fetal body (+60%; P <.001), heart (+167%; P <.05), and adrenals (+229%; P <.01) increased. Furthermore, during asphyxia circulatory centralization was impaired considerably in LPS-treated fetuses, and there was clear evidence of circulatory decentralization. This decentralization caused a severe decrease in cerebral oxygen delivery by 70%. Within 30 minutes after induction of asphyxia five of seven LPS-treated fetuses died, whereas all control fetuses recovered completely. Endotoxemia severely impaired fetal cardiovascular control during normoxia and asphyxia, resulting in a considerable decrease in cerebral oxygen delivery. These effects might have important effects in the development of fetal brain damage associated with intrauterine infection.

Angiotensin II and cardiovascular chemoreflex responses to acute hypoxia in late gestation fetal sheep.

1. In six intact and nine carotid sinus denervated (CSD) fetal sheep (125-128 days gestation) we measured heart rate (FHR), mean systemic arterial blood pressure (MAP), femoral and carotid blood flows (FBF and CBF), and femoral and carotid vascular resistances (FVR and CVR). Three experiments were conducted on successive days: normoxia followed by acute isocapnic hypoxia (Pa,O2 to ca 12 mmHg) with infusion of vehicle (HV experiment), the same protocol but with infusion of the angiotensin converting enzyme (ACE) inhibitor, captopril (HC experiment), and normoxia alone with captopril infusion (NC experiment). Plasma angiotensin II concentration ([AII]) was measured in these fetuses, and in a separate group of fetuses (n = 5) that were infused with the nitric oxide (NO) synthesis inhibitor N G-nitro-L-arginine methyl ester (L-NAME) or saline vehicle. 2. During normoxia, cardiovascular parameters and plasma [AII] were unaltered by captopril infusion, apart from a fall in MAP (NC experiment only, P < 0.05) and FHR (HC experiment only, P < 0.05) in intact and CSD fetuses, respectively. No differences were observed between intact and CSD groups. 3. At the onset of hypoxia the rapid initial fall in FHR and rise in FVR was attenuated in CSD fetuses. In all fetuses FHR returned towards prehypoxic levels as hypoxia continued. In contrast, during hypoxia with vehicle infusion (HV experiment) plasma [AII] rose to a similar level in intact and CSD fetuses. 4. In both intact and CSD fetuses, the rise in [AII] during hypoxia was blocked by captopril or L-NAME infusion. In CSD, but not intact, fetuses infused with captopril the rise in MAP was absent, and the fall in FBF and rise in FVR did not reach significance during hypoxia. 5. Thus, during normoxia CSD alone, or combined with ACE inhibition, does not consistently alter basal cardiovascular control in the late gestation fetus. The rise in [AII] during hypoxia is not mediated by carotid reflexes but may involve NO-dependent mechanisms. In intact fetuses, AII does not appear to be pivotal in cardiovascular control during hypoxia. It is only when carotid reflex mechanisms are removed that a role for AII in the regulation of MAP and peripheral blood flow during hypoxia becomes apparent. These findings lend weight to the idea of multiple mechanisms of fetal cardiovascular control during hypoxia.

Do we now understand the control of the fetal circulation?

Physiological research has now given us a reasonably complete picture of fetal cardiovascular control in late gestation, especially with respect to the responses to acute hypoxaemia. Reflex, endocrine and auto/paracrine mechanisms all play a part. This review questions how complete our knowledge is when we address the clinically important issues of the influence of gestational age, sustained hypoxia and the effects of nutrition in altering the programming of cardiovascular development.

Angiotensin mediated interaction of fetal kidney and placenta in the control of fetal arterial pressure and its role in hydrops fetalis

Fetal cardiovascular control is effected by an interaction of the fetal somatic and placental circulations. Three primary regulatory mechanisms are involved: transplacental transfer of extracellular fluid, driven by a difference in hydrostatic and oncotic pressures; modulation of fetal placental and somatic vascular resistances by means of blood pressure controlled production of angiotensin; and somatic autoregulation of flow. A systems analysis incorporates these and other fetal cardiovascular functions and this analysis was modelled for computer simulation. Given physiologically plausible values for known cardiovascular parameters in the fetal sheep, the model reproduced in detail a variety of experimental protocols with known outcomes; these included the normal fetus, the fetus after bilateral nephrectomy, the nephrectomized fetus infused with angiotensin, the intact fetus infused with NaCl solutions, the fetus with lymphatic obstruction and the severely anaemic fetus. The systems analysis demonstrated that fetal cardiac failure constituted the strongest stimulus for the formation of fetal oedema of any tested pathological intervention.

Fetal heart rate and neonatal condition related to epidural analgesia in women reaching the second stage of labour

The relationship between epidural analgesia and a number of labour and delivery factors, relevant to fetal and neonatal condition, was considered in a prospective study of 200 labours reaching the second stage of labour. The group was representative of the hospital population with regard to the proportion of nulliparous women, the incidence of instrumental vaginal deliveries and the incidence of epidural analgesia (37%). The 8% of labours requiring fetal blood sampling during the first stage, and the labours with fetal heart rate (FHR) decelerations in the hour prior to second stage (25%) and during pushing (50%) were significantly more likely to have been given an epidural. Nulliparity (55%), induced labour (34%), a first stage longer than eight hours (37%), a second stage longer than 60 min (43%), maternal pushing for longer than 36 min (50%), forceps delivery (28%) and a 1 min Apgar score less than 7 (12%) were also factors associated with significantly higher rates of epidural analgesia whereas meconium (15%), a small baby (16%) and umbilical arterial metabolic acidaemia (13%) were not. FHR decelerations in labours reaching the second stage with an epidural reflect adjustments to fetal cardiovascular control and not acidaemia.

Nature of fetal adaptation to the uterine environment: a problem of sensory deprivation

0 B S T E T R I c I A N s are concerned with fetal cardiovascular physiology whenever they listen to a fetal heart. The problem is to distinguish between “normal” and “distress” situations. With knowledge only of the physiology of the adult as a guide, it is little wonder that reliable criteria of fetal distress are not readily available. The purpose of this paper is to set forth the character of fetal cardiovascular control and to provide a basis for the interpretation of it. With this new concept in mind, the problems of intrauterine fetal life and of neonatal adjustments after birth come more clearly into view. With the fetus in utero, attention focuses on the effects of the loss of gravitational pull on the body. The more fundamental question involved is the basic physiology of antigravity mechanisms upon the body. From this \;iewpoint, the entire spectrum of the consequences of weightIessness on the organism may be seen. Then evidence affirming the broad concept of sensory deprivation in general upon the body, and of antigrakrity deprivation in particular, may be looked for. In their book, Kybunetics of N&u,-al Systems,’ D. and K. Stanley-Jones establish a case for the concept that physiologic systems which are in a state of dynamic equilibrium-as are all living things---arc under the control of built-in mechanisms